tbuckley/cabot-search huggingface dataset:
Analysis of Time to the Hospital and Ambulance Use Following a Stroke Community Education Intervention in China
Authors: Jing Yuan, Minghui Li, Yang Liu, Xiaomo Xiong, Zhengbao Zhu, Fangyu Liu, Yong Wang, Wei Hu, Z. Kevin Lu, Renyu Liu, Jing Zhao
Journal: JAMA Network Open (2022)

Prehospital delay (time from symptom onset of stroke to the door of a hospital) in patients with stroke is long in China. With the goal of improving public awareness and knowledge of stroke recognition, Stroke 1-2-0 was developed in China as an education program to prompt rapid response to the onset of stroke based on clinical practice in China, and examination of its outcomes is needed.To investigate the association of the Stroke 1-2-0 educational campaign with prehospital delay for patients with ischemic stroke.In a population-based cross-sectional study, all patients with ischemic stroke events were admitted to the Minhang Hospital, which is the only tertiary care hospital with a stroke center that provides acute stroke care in Xinzhuang county, Shanghai, China. The study period was from January 1, 2016, to December 31, 2019, and data analysis was performed from January 1 to July 31, 2021.A multifaceted Stroke 1-2-0 educational campaign comprising slides, videos, brochures, and posters distributed in the community.Proportion of patients with hospital arrival within 3 hours and use of an ambulance to seek medical care, as well as the odds of seeking medical attention within 3 hours after the stroke before vs after initiation of the multifaceted educational campaign.A total of 2857 patients (1774 men [62.1%]; mean [SD] age, 69.83 [12.66] years) with stroke were identified, including 503 in the precampaign period and 2354 in the postcampaign period. Following the multifaceted campaign, the median (IQR) prehospital delay time decreased from 18.72 (7.44-27.84) hours to 6.00 (2.00-16.35) hours (P < .001). After the implementation of the Stroke 1-2-0 campaign, the proportion of patients with hospital arrival time within 3 hours increased from 5.8% to 33.4% (P < .001) and use of an ambulance increased from 3.2% to 30.6% (P < .001). In an interrupted time series analysis, the initiation of the Stroke 1-2-0 campaign was associated with significantly increased odds of arriving at the hospital within 3 hours (odds ratio, 8.01; 95% CI, 7.17-8.95; P < .001) and use of an ambulance (odds ratio, 9.41; 95% CI, 8.24-10.74; P < .001).The persistent multifaceted campaign using the Stroke 1-2-0 program was associated with reduced prehospital delay and improved timely arrival rate and ambulance arrival rate for patients with stroke. These findings suggest that Stroke 1-2-0 can be adopted in other regions of China to possibly improve health outcomes and reduce clinical burdens for all patients with stroke.
Bimodal Gene Expression in Patients with Cancer Provides Interpretable Biomarkers for Drug Sensitivity
Authors: Wail Ba-Alawi, Sisira Kadambat Nair, Bo Li, Anthony Mammoliti, Petr Smirnov, Arvind Singh Mer, Linda Z. Penn, Benjamin Haibe-Kains
Journal: Cancer Research (2022)

Abstract Identifying biomarkers predictive of cancer cell response to drug treatment constitutes one of the main challenges in precision oncology. Recent large-scale cancer pharmacogenomic studies have opened new avenues of research to develop predictive biomarkers by profiling thousands of human cancer cell lines at the molecular level and screening them with hundreds of approved drugs and experimental chemical compounds. Many studies have leveraged these data to build predictive models of response using various statistical and machine learning methods. However, a common pitfall to these methods is the lack of interpretability as to how they make predictions, hindering the clinical translation of these models. To alleviate this issue, we used the recent logic modeling approach to develop a new machine learning pipeline that explores the space of bimodally expressed genes in multiple large in vitro pharmacogenomic studies and builds multivariate, nonlinear, yet interpretable logic-based models predictive of drug response. The performance of this approach was showcased in a compendium of the three largest in vitro pharmacogenomic datasets to build robust and interpretable models for 101 drugs that span 17 drug classes with high validation rates in independent datasets. These results along with in vivo and clinical validation support a better translation of gene expression biomarkers between model systems using bimodal gene expression. Significance: A new machine learning pipeline exploits the bimodality of gene expression to provide a reliable set of candidate predictive biomarkers with a high potential for clinical translatability.
Building digital twins of the human immune system: toward a roadmap
Authors: R. Laubenbacher, A. Niarakis, T. Helikar, G. An, B. Shapiro, R. S. Malik-Sheriff, T. J. Sego, A. Knapp, P. Macklin, J. A. Glazier
Journal: npj Digital Medicine (2022)

Abstract Digital twins, customized simulation models pioneered in industry, are beginning to be deployed in medicine and healthcare, with some major successes, for instance in cardiovascular diagnostics and in insulin pump control. Personalized computational models are also assisting in applications ranging from drug development to treatment optimization. More advanced medical digital twins will be essential to making precision medicine a reality. Because the immune system plays an important role in such a wide range of diseases and health conditions, from fighting pathogens to autoimmune disorders, digital twins of the immune system will have an especially high impact. However, their development presents major challenges, stemming from the inherent complexity of the immune system and the difficulty of measuring many aspects of a patient’s immune state in vivo. This perspective outlines a roadmap for meeting these challenges and building a prototype of an immune digital twin. It is structured as a four-stage process that proceeds from a specification of a concrete use case to model constructions, personalization, and continued improvement.
Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy
Authors: Lawrence P. Andrews, Anthony R. Cillo, Lilit Karapetyan, John M. Kirkwood, Creg J. Workman, Dario A.A. Vignali
Journal: Clinical Cancer Research (2022)

Abstract Immunotherapy targeting coinhibitory receptors has been highly successful in treating a wide variety of malignancies; however, only a subset of patients exhibits durable responses. The first FDA-approved immunotherapeutics targeting coinhibitory receptors PD1 and CTLA4, alone or in combination, significantly improved survival but were also accompanied by substantial toxicity in combination. The third FDA-approved immune checkpoint inhibitor targets LAG3, a coinhibitory receptor expressed on activated CD4+ and CD8+ T cells, especially in settings of long-term antigenic stimulation, such as chronic viral infection or cancer. Mechanistically, LAG3 expression limits both the expansion of activated T cells and the size of the memory pool, suggesting that LAG3 may be a promising target for immunotherapy. Importantly, the mechanism(s) by which LAG3 contributes to CD8+ T-cell exhaustion may be distinct from those governed by PD1, indicating that the combination of anti-LAG3 and anti-PD1 may synergistically enhance antitumor immunity. Clinical studies evaluating the role of anti-LAG3 in combination with anti-PD1 are underway, and recent phase III trial results in metastatic melanoma demonstrate both the efficacy and safety of this combination. Further ongoing clinical trials are evaluating this combination across multiple tumor types and the adjuvant setting, with accompanying translational and biomarker-focused studies designed to elucidate the molecular pathways that lead to improved antitumor T-cell responses following dual blockade of PD1 and LAG3. Overall, LAG3 plays an important role in limiting T-cell activation and has now become part of the repertoire of combinatorial immunotherapeutics available for the treatment of metastatic melanoma.
Acute inflammatory response via neutrophil activation protects against the development of chronic pain
Authors: Marc Parisien, Lucas V. Lima, Concetta Dagostino, Nehme El-Hachem, Gillian L. Drury, Audrey V. Grant, Jonathan Huising, Vivek Verma, Carolina B. Meloto, Jaqueline R. Silva, Gabrielle G. S. Dutra, Teodora Markova, Hong Dang, Philippe A. Tessier, Gary D. Slade, Andrea G. Nackley, Nader Ghasemlou, Jeffrey S. Mogil, Massimo Allegri, Luda Diatchenko
Journal: Science Translational Medicine (2022)

The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) and performed transcriptome-wide analysis in peripheral immune cells of 98 participants with acute LBP, followed for 3 months. Transcriptomic changes were compared between patients whose LBP was resolved at 3 months with those whose LBP persisted. We found thousands of dynamic transcriptional changes over 3 months in LBP participants with resolved pain but none in those with persistent pain. Transient neutrophil-driven up-regulation of inflammatory responses was protective against the transition to chronic pain. In mouse pain assays, early treatment with a steroid or nonsteroidal anti-inflammatory drug (NSAID) also led to prolonged pain despite being analgesic in the short term; such a prolongation was not observed with other analgesics. Depletion of neutrophils delayed resolution of pain in mice, whereas peripheral injection of neutrophils themselves, or S100A8/A9 proteins normally released by neutrophils, prevented the development of long-lasting pain induced by an anti-inflammatory drug. Analysis of pain trajectories of human subjects reporting acute back pain in the UK Biobank identified elevated risk of pain persistence for subjects taking NSAIDs. Thus, despite analgesic efficacy at early time points, the management of acute inflammation may be counterproductive for long-term outcomes of LBP sufferers.
Intrinsic transcriptional heterogeneity in neuroblastoma guides mechanistic and therapeutic insights
Authors: Noha A.M. Shendy, Mark W. Zimmerman, Brian J. Abraham, Adam D. Durbin
Journal: Cell Reports Medicine (2022)

Cell state is controlled by master transcription factors (mTFs) that determine the cellular gene expression program. Cancer cells acquire dysregulated gene expression programs by mutational and non-mutational processes. Intratumoral heterogeneity can result from cells displaying distinct mTF-regulated cell states, which co-exist within the tumor. One archetypal tumor associated with transcriptionally regulated heterogeneity is high-risk neuroblastoma (NB). Patients with NB have poor overall survival despite intensive therapies, and relapsed patients are commonly refractory to treatment. The cellular populations that comprise NB are marked by different cohorts of mTFs and differential sensitivity to conventional therapies. Recent studies have highlighted mechanisms by which NB cells dynamically shift the cell state with treatment, revealing new opportunities to control the cellular response to treatment by manipulating cell-state-defining transcriptional programs. Here, we review recent advances in understanding transcriptionally defined cancer heterogeneity. We offer challenges to the field to encourage translation of basic science into clinical benefit.
Very Elevated High-Density Lipoprotein Cholesterol and Mortality—The Good Gone Bad?
Authors: Sadiya S. Khan, Gregg C. Fonarow
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
<i>Vital Signs</i>: Changes in Firearm Homicide and Suicide Rates — United States, 2019–2020
Authors: Scott R. Kegler, Thomas R. Simon, Marissa L. Zwald, May S. Chen, James A. Mercy, Christopher M. Jones, Melissa C. Mercado-Crespo, Janet M. Blair, Deborah M. Stone, Phyllis G. Ottley, Jennifer Dills
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Introduction:The majority of homicides (79%) and suicides (53%) in the United States involved a firearm in 2020.High firearm homicide and suicide rates and corresponding inequities by race and ethnicity and poverty level represent important public health concerns.This study examined changes in firearm homicide and firearm suicide rates coinciding with the emergence of the COVID-19 pandemic in 2020.Methods: National vital statistics and population data were integrated with urbanization and poverty measures at the county level.Population-based firearm homicide and suicide rates were examined by age, sex, race and ethnicity, geographic area, level of urbanization, and level of poverty.Results: From 2019 to 2020, the overall firearm homicide rate increased 34.6%, from 4.6 to 6.1 per 100,000 persons.The largest increases occurred among non-Hispanic Black or African American males aged 10-44 years and non-Hispanic American Indian or Alaska Native (AI/AN) males aged 25-44 years.Rates of firearm homicide were lowest and increased least at the lowest poverty level and were higher and showed larger increases at higher poverty levels.The overall firearm suicide rate remained relatively unchanged from 2019 to 2020 (7.9 to 8.1); however, in some populations, including AI/AN males aged 10-44 years, rates did increase. Conclusions and Implications for Public Health Practice:During the COVID-19 pandemic, the firearm homicide rate in the United States reached its highest level since 1994, with substantial increases among several population subgroups.These increases have widened disparities in rates by race and ethnicity and poverty level.Several increases in firearm suicide rates were also observed.Implementation of comprehensive strategies employing proven approaches that address underlying economic, physical, and social conditions contributing to the risks for violence and suicide is urgently needed to reduce these rates and disparities.
Challenges in the diagnosis and management of wound infection
Authors: Matthew Malone, Gregory Schultz
Journal: British Journal of Dermatology (2022)

Journal Article Challenges in the diagnosis and management of wound infection Get access Matthew Malone, Matthew Malone South West Sydney Limb Preservation and Wound Research South Western Sydney LHD Sydney NSW AustraliaInfectious Diseases and Microbiology, School of Medicine Western Sydney University Sydney NSW Australia Correspondence Matthew Malone. Email: matthew.malone@westernsydney.edu.au https://orcid.org/0000-0002-2946-8841 Search for other works by this author on: Oxford Academic Google Scholar Gregory Schultz Gregory Schultz Institute for Wound Research University of Florida Gainesville FL USA Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 187, Issue 2, 1 August 2022, Pages 159–166, https://doi.org/10.1111/bjd.21612 Published: 01 August 2022
Vaccine-induced T-cell responses against SARS-CoV-2 and its Omicron variant in patients with B cell–depleted lymphoma after CART therapy
Authors: Djordje Atanackovic, Tim Luetkens, Destiny Omili, Thierry Iraguha, Forat Lutfi, Nancy M. Hardy, Xiaoxuan Fan, Stephanie V. Avila, Kapil K. Saharia, Jennifer S. Husson, Silke V. Niederhaus, Philip Margiotta, Seung T. Lee, Jennie Y. Law, Heather D. Mannuel, Erica Vander Mause, Sherri Bauman, Patricia Lesho, Kim Hankey, John Baddley, Mehmet Kocoglu, Jean A. Yared, Aaron P. Rapoport, Saurabh Dahiya
Journal: Blood (2022)
Clinical Benefit Scales and Trial Design: Some Statistical Issues
Authors: Edward L Korn, Carmen J Allegra, Boris Freidlin
Journal: JNCI Journal of the National Cancer Institute (2022)

Recently developed clinical-benefit outcome scales by the European Society for Medical Oncology and the American Society of Clinical Oncology allow standardized objective evaluation of outcomes of randomized clinical trials. However, incorporation of clinical-benefit outcome scales into trial designs highlights a number of statistical issues: the relationship between minimal clinical benefit and the target treatment-effect alternative used in the trial design, designing trials to assess long-term benefit, potential problems with using a trial endpoint that is not overall survival, and how to incorporate subgroup analyses into the trial design. Using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale as a basis for discussion, we review what these issues are and how they can guide the choice of trial-design target effects, appropriate endpoints, and prespecified subgroup analyses to increase the chances that the resulting trial outcomes can be appropriately evaluated for clinical benefit.
Natural variation in Drosophila shows weak pleiotropic effects
Authors: Eirini Christodoulaki, Viola Nolte, Wei-Yun Lai, Christian Schlötterer
Journal: Genome biology (2022)

Abstract Background Pleiotropy describes the phenomenon in which a gene affects multiple phenotypes. The extent of pleiotropy is still disputed, mainly because of issues of inadequate power of analyses. A further challenge is that empirical tests of pleiotropy are restricted to a small subset of all possible phenotypes. To overcome these limitations, we propose a new measurement of pleiotropy that integrates across many phenotypes and multiple generations to improve power. Results We infer pleiotropy from the fitness cost imposed by frequency changes of pleiotropic loci. Mixing Drosophila simulans populations, which adapted independently to the same new environment using different sets of genes, we show that the adaptive frequency changes have been accompanied by measurable fitness costs. Conclusions Unlike previous studies characterizing the molecular basis of pleiotropy, we show that many loci, each of weak effect, contribute to genome-wide pleiotropy. We propose that the costs of pleiotropy are reduced by the modular architecture of gene expression, which facilitates adaptive gene expression changes with low impact on other functions.
Coronary Microvascular Dysfunction Is Associated With a Worse Cardiac Phenotype in Patients With Fabry Disease
Authors: Francesca Graziani, Lucia Leccisotti, Rosa Lillo, Isabella Bruno, Gessica Ingrasciotta, Antonio M. Leone, Rocco A. Montone, Riccardo Marano, Giuseppe Rovere, Luca Indovina, Antonia Camporeale, Maurizio Pieroni, Alessandro Giordano, Raffaele Manna, Antonella Lombardo, Massimo Massetti, Gaetano A. Lanza, Filippo Crea
Journal: JACC. Cardiovascular imaging (2022)
Abstract IA007: Outcompeting cancer in the intestine
Authors: Louis Vermeulen
Journal: Cancer Research (2022)

Abstract Cancers develop in a stepwise fashion as mutations in oncogenes and tumor suppressor genes accumulate. The mutations provide the cells in which they occur typically an advantage over the surrounding wild type neighbors, resulting in clonal expansion. Understanding the nature of the competitive benefit of oncogenic cells might result in the identification of targets for prevention of cancer. In particular in individuals affected by hereditary cancer syndromes, in which the initiating mutations are well-described, this is a promising strategy. I will discuss our work on intestinal carcinogenesis and the impact on stem cell properties of mutations associated with familial cancer syndromes affecting the gut. In particular I will discuss how inactivation of the tumor suppressor gene APC, which is affected in individuals suffering from Familial Adenomatous Polyposis (FAP), generates supercompetitor cells that actively suppress their neighbors. As we will see, the uncovered mechanism directly suggests a potent chemopreventive strategy that is currently being tested in a proof-of-concept clinical trial in FAP individuals. Citation Format: Louis Vermeulen. Outcompeting cancer in the intestine [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA007.
Internalization of targeted microbubbles by endothelial cells and drug delivery by pores and tunnels
Authors: Inés Beekers, Simone A.G. Langeveld, Bram Meijlink, Antonius F.W. van der Steen, Nico de Jong, Martin D. Verweij, Klazina Kooiman
Journal: Journal of Controlled Release (2022)

Ultrasound insonification of microbubbles can locally enhance drug delivery by increasing the cell membrane permeability. To aid development of a safe and effective therapeutic microbubble, more insight into the microbubble-cell interaction is needed. In this in vitro study we aimed to investigate the initial 3D morphology of the endothelial cell membrane adjacent to individual microbubbles (n = 301), determine whether this morphology was affected upon binding and by the type of ligand on the microbubble, and study its influence on microbubble oscillation and the drug delivery outcome. High-resolution 3D confocal microscopy revealed that targeted microbubbles were internalized by endothelial cells, while this was not the case for non-targeted or IgG1-κ control microbubbles. The extent of internalization was ligand-dependent, since αvβ3-targeted microbubbles were significantly more internalized than CD31-targeted microbubbles. Ultra-high-speed imaging (~17 Mfps) in combination with high-resolution confocal microscopy (n = 246) showed that microbubble internalization resulted in a damped microbubble oscillation upon ultrasound insonification (2 MHz, 200 kPa peak negative pressure, 10 cycles). Despite damped oscillation, the cell's susceptibility to sonoporation (as indicated by PI uptake) was increased for internalized microbubbles. Monitoring cell membrane integrity (n = 230) showed the formation of either a pore, for intracellular delivery, or a tunnel (i.e. transcellular perforation), for transcellular delivery. Internalized microbubbles caused fewer transcellular perforations and smaller pore areas than non-internalized microbubbles. In conclusion, studying microbubble-mediated drug delivery using a state-of-the-art imaging system revealed receptor-mediated microbubble internalization and its effect on microbubble oscillation and resulting membrane perforation by pores and tunnels.
Risk and protective factors for SARS-CoV-2 reinfections, surveillance data, Italy, August 2021 to March 2022
Authors: Chiara Sacco, Daniele Petrone, Martina Del Manso, Alberto Mateo-Urdiales, Massimo Fabiani, Marco Bressi, Antonino Bella, Patrizio Pezzotti, Maria Cristina Rota, Flavia Riccardo
Journal: Eurosurveillance (2022)

We explored the risk factors associated with SARS-CoV-2 reinfections in Italy between August 2021 and March 2022. Regardless of the prevalent virus variant, being unvaccinated was the most relevant risk factor for reinfection. The risk of reinfection increased almost 18-fold following emergence of the Omicron variant compared with Delta. A severe first SARS-CoV-2 infection and age over 60 years were significant risk factors for severe reinfection.